Combination chemotherapy

ABSTRACT

Suramin in combination with a vinca alkaloid or estramustine is synergistic for treating cancer.

BACKGROUND OF THE INVENTION

The invention concerns a method for treating tumors utilizing acombination of known oncolytic agents. The use of the agents togetherprovides unexpectedly greater efficacy than employing the single agentsalone.

Cancer chemotherapy has advanced dramatically in recent years. Manytumors can be effectively treated and irradicated utilizing compoundswhich are either naturally occurring products or synthetic agents.Cancer chemotherapy often entails use of a combination of agents,generally as a means of reducing the toxic effects that are oftenencountered with the individual agents when used alone.

We have now discovered a unique combination of known oncolytic agentswhich exhibit a dramatic synergistic effect. The combination utilizesthe agent suramin, together with either a vinca alkaloid orestramustine. The combination is especially effective in treating bothprostate and breast cancer.

Suramin is the hexasodium salt of a polysulfonated naphthylurea, namely8,8'-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimine]]bis-1,3,5-naphthalenetrisulfonicacid. It also is known as Germanin, Belgenyl, Maphuride, and Antrypol,hexasodium salt. Suramin has been utilized clinically since the 1920s asan antiparasitic agent, and more recently has been shown to be active inthe treatment of metastatic cancer; Stein, et al., J. Clin. Oncology1989;7(4):499-508. Fruehauf, et al., reported that the antitumoractivity of suramin is potentiated by doxorubicin, especially againsthuman prostate cell line PC-3; J. Nat. Can. Inst. 1990;82(14):1206-9.Suramin is known to have several toxic effects in some patients,including adrenal insufficiency, neuropathy, coagulopathy, hypocalcemia,and neurotoxic effects. Occurrence of these adverse effects oftenrequires limiting the dose of suramin, or withdrawing treatmentcompletely.

Several vinca alkaloids are commercially utilized to treat certaincancers. Vinblastine, for example, is an alkaloid isolated from Vincarosa. Vinblastine sulfate is utilized clinically to treat Hodgkin'sdisease, lymphocytic lymphoma, histiocytic lymphoma, and breast cancer.Vincristine is another antitumor alkaloid isolated from Vinca rosa.Vindesine is a synthetic derivative of vinblastine. These and othervinca alkaloids are known to have a variety of antineoplasticactivities.

Estramustine is an estradiol derivative, namely estradiol3-bis(2-chloroethyl)carbamate. It is utilized commercially as thephosphate sodium salt, and is indicated in the palliative treatment ofpatients with metastatic and/or progressive carcinoma of the prostate.

An object of this invention to provide a method for treating cancers,especially prostate cancer and breast cancer, with a combinationcomprising suramin together with either a vinca alkaloid orestramustine. A further object is to provide a composition comprisingsuramin and either a vinca alkaloid or estramustine.

SUMMARY OF THE INVENTION

This invention relates to a synergistic combination of antineoplasticagents, and to a method for treating tumors comprising administering thecombination. The invention more particularly provides a compositioncomprising, as a first component, suramin, preferably as the hexasodiumsalt, and as a second component either a vinca alkaloid or estramustine.

The compositions of this invention consist essentially of the aboveactive ingredients, or suitable salts thereof, together with commonexcipients, diluents, and carriers.

A preferred composition comprises suramin sodium (the hexasodium salt),together with vinblastine sulfate. Another preferred compositioncomprises suramin sodium together with estramustine phosphate sodium.

In a further embodiment of the invention, we provide a method fortreating cancer comprising administering to an animal in need oftreatment an effective amount of a combination of suramin and either avinca alkaloid or estramustine.

A preferred method embraces treatment of prostate cancer and breastcancer.

A further preferred method employs an antitumor amount of suramin sodiumand an effective amount of vinblastine sulfate.

Another preferred method employs an antitumor amount of suramin sodiumand an antitumor amount of estramustine phosphate sodium.

DETAILED DESCRIPTION OF THE INVENTION

The compounds to be utilized in the method of this invention will beadministered in doses commonly employed clinically. Suramin will beadministered, for example, at doses from about 275 mg/m² to about 1000mg/m², preferably from about 350 mg/m² to about 600 mg/m². Ideally,suramin will be administered at a dose which will produce plasma levelsof about 100 to about 300 μg/mL. Suramin typically is administered byintravenous infusion over a 12- to 16-week period, as needed to maintainthe indicated plasma levels. Suramin will be administered at about thesame dose levels and frequency according to this invention.

The vinca alkaloid antitumor agents are generally administered by IVinjection at doses of about 2 mg/m² to about 20 mg/m², generally aboutonce each week during a treatment cycle of about 12 to 16 weeks. Forexample, vinblastine sulfate generally is administered to adults at adose of about 3 to about 4 mg/m² in Week 1 of treatment. Doses generallyare increased, for example, to about 5.5 mg/m² in Week 2, about 7.4mg/m² in Week 3, about 9 mg/m² in Week 4, and about 1 mg/m² in Week 5and thereafter during the course of treatment.

Estramustine generally is utilized clinically as the phosphate sodiumsalt. It usually is administered orally at a daily dose of about 10 toabout 20 mg per kilogram of body weight. The doses often are given as 3to 4 divided doses over a 12- to 16-hour period. According to thisinvention, estramustine will be administered at a dose of about 10 toabout 20 mg/kg of animal body weight.

The combination of suramin with either a vinca alkaloid or estramustinehas been found to have an unusually greater effect than expected. Thecombination exhibits a much greater than additive effect.

The combination provided by this invention has been evaluated in severalassay systems, and the data has been analyzed utilizing a standardprogram for quantifying synergism, additivism, and antagonism amonganticancer agents. The program is that described by Chou and Talalay, in"New Avenues in Developmental Cancer Chemotherapy" Academic Press, 1987,Chapter 2.

The method is based on the median-effect principle of the mass-actionlaw using an enzyme kinetic system as a model. The equation is simpleand describes the relationships between dose and effect regardless ofthe shape of the dose-effect curve. Two basic equations constitute thepillars of this methodology. To relate dose and effect for a single drugin the simplest way possible, the median-effect equation derived by Chouis given by:

    f.sub.a /f.sub.u =(D/D.sub.m).sup.m

or

    D=D.sub.m [f.sub.a /(1-f.sub.a ].sup.1/m

where the right side represents the dose and the left side representsthe effect, in which f_(a) and f_(u) are the fractions affected andunaffected, respectively, D is the dose, D_(m) is the median-effect dosesignifying the potency, and m is a coefficient signifying the shape ofthe dose-effect curve. From this equation Chou and Talalay derived thegeneral equation for 2 or more drugs: ##EQU1## where m=1 is forfirst-order Michaelis-Menten-type kinetics and m>1 (or m<1) is forhigher order (or lower order) Hill-type kinetics. When alpha=0, thethird term on the right side disappears and when alpha=1, the third termis conserved. Alpha=0 is used for mutually exclusive drugs and alpha=1is used for mutually nonexclusive drugs. For drugs that have the same orsimilar modes of action, the effects of both drugs are mutuallyexclusive. For drugs that have different modes of action or actindependently, the effects of both drugs are mutually nonexclusive.Since we do not know the mechanism of action of suramin, we analyze ourdata by both parameters.

A plot of fraction affected (F_(a)) versus combination index (CI) iscalled the F_(a) -CI plot. This plot indicates synergism, additivity, orantagonism of 2 drugs at various effect levels in a mixture that isserially diluted. If several mixtures are made, it is possible toestimate the optimal combination ratio for maximal synergy. Differenteffect levels usually give different degress of synergism, additivism,or antagonism. CI values<1 indicate synergism; CI values≦1 indicateantagonism, and CI values that are 1 or hover around 1 indicateadditivity. For anticancer agents, synergism at high effect levels(F_(a)) is clinically more relevant than synergism at low F_(a) levels.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that suramin is synergistic with vinblastine in prostatecancer cells.

FIG. 2 shows that suramin is additive with estramustine in prostatecancer cells.

FIG. 3 shows that suramin is antagonistic to the activity of taxol inprostate cancer cells.

FIG. 4 shows that suramin is synergistic with vinblastin in breastcancer cells.

FIG. 5 shows that high doses of suramin are synergistic with high dosesof estramustine in breast cancer cells.

FIG. 6 shows that suramin antagonizes the activity of taxol in breastcancer cells.

In human prostate cancer PC-3 cells, analysis of the combination ofsuramin and vinblastine using F_(a) -CI plots demonstrates synergism atthe higher F_(a) values (FIG. 1). The combination of suramin plusestramustine (Emcyt) appears to be additive by the same analysis (FIG.2). In contrast, a suramin-taxol combination is antagonistic againstPC-3 cells (FIG. 3).

In human breast cancer MCF-7 cells, analysis of the combination ofsuramin and vinblastine using F_(a) -CI plots also demonstrates verystrong synergism at all concentrations of both drugs (FIG. 4). Thecombination of suramin and estramustine is also synergistic at thehighest effect concentrations (FIG. 5). As in PC-3 cells, thecombination of suramin and taxol showed strong antagonism against MCF-7cells (FIG. 6).

Thus, we have found that suramin is synergistic with vinblastine againstboth human prostate and breast cancer cells in vitro. In addition, weobserved that suramin and estramustine were also synergistic in MCF-7cells and additive in activity against PC-3 cells. It is conceivablethat nonoverlapping toxicities of both estramustine and suramin maytranslate into clear synergy when this combination is given in theclinical setting.

In contrast, suramin in combination with microtubule inhibitors such astaxol, navelbine, or colchicine proved to be antagonistic. Similarly,combinations of suramin with polyamine inhibitors were antagonistic,whereas suramin with carboplatinum was merely additive.

The foregoing data establish an unexpectedly favorable interactionbetween suramin and either a vinca alkaloid antitumor agent orestramustine. Accordingly, this invention provides a method of treatingprostate cancer and breast cancer comprising administering suramin in aregimen together with either a vinca alkaloid antitumor agent orestramustine. The combination generally will include each activeingredient packaged separately, thereby avoiding any interaction betweenthe agents prior to administration. If desired, the individuallypackaged drugs can be placed in a single carton, thereby providingconvenience to the attending physician or medical attendant.

We claim:
 1. A combination of antineoplastic agents useful for treatingprostate cancer or breast cancer comprising effective synergisticamounts of suramin and vinblastine.
 2. A combination of claim 1employing suramin as the hexasodium salt.
 3. A combination of claim 2employing vinblastine as a pharmaceutically acceptable salt thereof. 4.A combination of claim 3 employing vinblastine sulfate.
 5. A method oftreating prostate cancer comprising administering to an animal in needof treatment an effective amount of a combination of claim
 1. 6. Amethod of claim 5 employing suramin hexasodium in combination withvinblastine sulfate.
 7. A method of treating breast cancer comprisingadministering to an animal in need of treatment an effective amount of acombination of claim
 1. 8. A method of claim 7 employing suraminhexasodium in combination with vinblastine sulfate.